This proposal is a competing continuation of the NIH grant RO1 CA89225. The long term-goal of this project is to improve the therapeutic outcomes in cancer via enhanced drug delivery of chemotherapeutic agents to multidrug resistant (MDR) tumors. This goal is achieved by combining anti-cancer drugs and block copolymers of poly(ethylene oxide) and polypropylene oxide) ("Pluronics"). Previous studies have shown that Pluronics 1) inhibit ATPase activity of P-glycoprotein (Pgp) and 2) deplete ATP in MDR cells. The synergy between these two effects results in the chemosensitization of MDR tumors. The objective of this proposal is i) to elucidate the mechanisms of Pgp inhibition and ATP depletion by Pluronic in MDR cells; ii) to evaluate these mechanisms in vivo by examining whether Pluronic induces Pgp inhibition and ATP depletion in MDR tumors; and iii) to determine whether Pluronic can prevent the appearance of the MDR in tumors induced by drugs. This proposal will (1) determine how Pluronics interact with Pgp in the membranes of MDR cells using the fluorescence resonance energy transfer (FRET) and photosensitized labeling; (2) determine how Pluronics affect respiration in the mitochondria of MDR cells by characterizing the effects of Pluronics on the activities of the respiratory chain complexes and the mitochondria! H+-ATPase; (3) determine whether Pluronics (a) increase the uptake of a Pgp probe within tumors (using single-photon emission computerized tomography (A- SPECT)), and (b) inhibit the energy metabolism in tumors (using 31P-magnetic resonance spectroscopy (31P-MRS)); and, finally, (4) determine whether Pluronics can prevent the development of the drug resistance in tumors induced by anti-cancer drugs, doxorubicin and paclitaxel. As a result, the critical knowledge will be acquired on the activities of a novel chemotherapeutic agent composition that has promise in improving treatment of cancer patents.